This project will examine the role of the innate immune system in the pathophysiology of the viral hemorrhagic fevers. Two viruses which are potential agents of bioterrorism, will be studied: 1) Ebola virus, a filovirus, which induces an acute illness characterized by fever, leucopenia, shock, and death, and 2) Lymphocytic Choriomeningitis Virus LCMV an arenavirus which causes an illness characterized by leucopenia and thrombocytopenia in mice and meningitis in humans. The high mortality rate associated with Ebola infection has been demonstrated to be directly associated with cytokine release which occurs after viral infection of macrophages. The mechanism by which Ebola induces this cytokine response will be defined and compounds will be screened for their ability to inhibit this activity. Preliminary data indicate a major role for Toll Like Receptor 2 (TLR-2) and CD14 in the cytokine response to LCMV. TLR-2 and CD14 are pattern recognition proteins whose role in bacterial sepsis has been recently defined. Both have also been associated with the immune responses to viruses. Using transfected cell lines and available knockout mice the mechanism by which these proteins affect both initial induction of cytokines as well as the subsequent immune responses to LCMV and Ebola virus will be defined. The specific TLRs (and other "pattern recognition proteins") involved in these responses as well as their interactions will be studied. The effect of these early recognition events on long-term Band T cell immunity will be investigated. These studies will result in a better understanding of the role that the innate immune system has in mediating the pathophysiology of hemorrhagic fever viruses and should lead to new therapeutic approaches to these diseases.